Stem cell therapy for myocardial infarction has been proposed as a restorative therapy to limit progressive remodeling. However, its therapeutic benefit is still controversial largely because most studies failed to account for the variations in the initial infarct size and the extent of ventricular remodeling on the therapeutic outcome;the fate (survival and differentiation status) of the grafted cells is not clear either. Therefore, the overall goal of this proposal is to develop a multi-modality non-invasive imaging approach to best assess these critical parameters. This system would allow assessment of the survival and differentiation of grafted stem cells longitudinally in the same animals, on which the extent of initial impairment and experimental recovery are evaluated. Specifically, two reporter genes (one for cell survival and the other for differentiation) will be introduced: the survival marker is always "on" as long as the cell is alive, whereas the differentiation marker is NOT turned on until the cardiac differentiation occurs in the cell. After stem cells are grafted, survival fraction will be quantified by the expression of the reporter gene associated with the surviving cells, using radionuclide imaging (PET) while cardiac differentiation of these cells will be detected / monitored by optical imaging. Tagged or displacement encoded MRI will be used to quantify the regional myocardial contractile function and to document the functional loss or gain during LV remodeling in response to stem cell grafting. This strategy aims to maximize the sensitivity and spatial resolution necessary for specific measurements. By using these imaging modalities in concert, a cohesive picture of stem cell survival, differentiation in the infarcted myocardium and their therapeutic benefits will be obtained to address critical issues regarding the fate and therapeutic mechanism of stem cells, i.e., do the grafted cells contribute to the improvement of contractile function or they primarily provide structural support to "stiffen" the infarcted heart wall, thus reduce the wall-stress?